Sex differences in the associations of body size and body shape with platelets in the UK Biobank cohort

Background Obesity is accompanied by low-grade inflammation and leucocytosis and increases the risk of venous thromboembolism. Associations with platelet count, however, are unclear, because several studies have reported positive associations only in women. Associations with body shape are also unclear, because waist and hip circumferences reflect overall body size, as well as body shape, and are correlated strongly positively with body mass index (BMI). Methods We evaluated body shape with the allometric body shape index (ABSI) and hip index (HI), which reflect waist and hip size among individuals with the same weight and height and are uncorrelated with BMI. We examined the associations of BMI, ABSI, and HI with platelet count, mean platelet volume (MPV), and platelet distribution width (PDW) in multivariable linear regression models for 125,435 UK Biobank women and 114,760 men. We compared men with women, post-menopausal with pre-menopausal women, and older (≥ 52 years) with younger (< 52 years) men. Results BMI was associated positively with platelet count in women, more strongly in pre-menopausal than in post-menopausal, and weakly positively in younger men but strongly inversely in older men. Associations of BMI with platelet count were shifted towards the inverse direction for daily alcohol consumption and current smoking, resulting in weaker positive associations in women and stronger inverse associations in men, compared to alcohol ≤ 3 times/month and never smoking. BMI was associated inversely with MPV and PDW in pre-menopausal women but positively in post-menopausal women and in men. ABSI was associated positively with platelet count, similarly in women and men, while HI was associated weakly inversely only in women. ABSI was associated inversely and HI positively with MPV but not with PDW and only in women. Platelet count was correlated inversely with platelet size and positively with leucocyte counts, most strongly with neutrophils. Conclusions Competing factors determine the associations of BMI with platelet count. Factors with sexually dimorphic action (likely thrombopoietin, inflammatory cytokines, or cortisol), contribute to a positive association, more prominently in women than in men, while age-dependent factors (likely related to liver damage and fibrosis), contribute to an inverse association, more prominently in men than in women. Supplementary Information The online version contains supplementary material available at 10.1186/s13293-023-00494-y.


S1
Sex differences in the associations of body size and body shape with platelets in the UK Biobank cohort Sofia Christakoudi, Konstantinos K. Tsilidis, Evangelos Evangelou, Elio Riboli Additional Tables   Table S1 Flow   If the participant was uncertain of the type of illness they had had, then they described it to the interviewer (a trained nurse) who attempted to place it within the coding tree. If the illness could not be located in the coding tree, then the interviewer entered a free-text description of it. These free-text descriptions were subsequently examined by a doctor and, where possible, matched to entries in the coding tree. Free-text descriptions which could not be matched with very high probability have been marked as "unclassifiable".  HRT -hormone replacement therapy; NSAID -nonsteroidal anti-inflammatory drugs; OC -oral contraceptives; Pre-MP -pre-menopausal women; Post-MP -post-menopausal women; SDstandard deviation; n (%) -number (percentage from total per column); # -tertile cut-offs for Townsend deprivation index (-3.298 and -1.067 for women; -3.295 and -0.975 for men). SDdifferences (95% CI) in platelet parameters per one SD increment of BMI from multivariable linear regression models including each platelet parameter as an outcome variable (sex-specific z-scores, following log-transformation) and BMI, ABSI, and HI as exposure variables (sex-specific z-scores), with adjustment for height, age, weight change (last year), smoking status (except for subgroups), alcohol consumption (except for subgroups), physical activity, Townsend deprivation index, region of the assessment centre, time of blood collection, fasting time, use of nonsteroidal antiinflammatory drugs, paracetamol use, menopausal status (women overall), hormonal replacement therapy use (women overall and Post-MP), oral contraceptives use and age at the last live birth (all women). Separate analyses were performed within subgroups by alcohol consumption and smoking status, individually for women and men. Plots are shown in Figure 1.

S7
p sex -p-value for the interaction term of BMI with sex, from a model including women (reference) and men, with adjustment for ABSI, HI, covariates (except female-specific), and including an interaction term between age and sex, to account for potential differences by menopausal status in women (p<1*10 -6 bold).
p women MP / men age -p-value for the interaction term of BMI with menopausal status, from a model including Pre-MP (reference) and Post-MP women, or of BMI with age (continuous), from a model including all men, with adjustment for ABSI, HI, and covariates (p<1*10 -6 bold).
W / M p-value (women / men) from likelihood ratio tests comparing models with and without an interaction term of BMI with either alcohol consumption or smoking status, separately for women and men, with adjustment for ABSI, HI, and covariates (p<1*10 -6 bold).
* p<0.05; ** p<0.001; *** p<1*10 -6 p-value from Wald test for the individual term.  SDdifferences (95% CI) in platelet parameters per one SD increment of ABSI or HI from multivariable linear regression models including each platelet parameter as an outcome variable (sex-specific z-scores, following log-transformation) and ABSI, HI, and body mass index (BMI) as exposure variables (sex-specific z-scores), with adjustment for height, age, weight change (last year), smoking status, alcohol consumption, physical activity, Townsend deprivation index, region of the assessment centre, time of blood collection, fasting time, use of nonsteroidal anti-inflammatory drugs, S10 paracetamol use, menopausal status (women overall), hormonal replacement therapy use (women overall and Post-MP), oral contraceptives use and age at the last live birth (all women). Plots are shown in Figure 2.

S9
p sex -p-values for the interaction terms of ABSI and HI with sex, from a model including women (reference) and men, with adjustment for BMI, covariates (except female-specific), and including an interaction term of age with sex, to account for potential differences by menopausal status in women (p<1*10 -6 bold).
p women MP -p-values for the interaction terms of ABSI and HI with menopausal status, from a model including Pre-MP (reference) and Post-MP women, with adjustment for BMI and covariates (p<1*10 -6 bold).
p men age -p-values for the interaction terms of ABSI and HI with age (continuous), from a model including all men, with adjustment for BMI and covariates (except female-specific) (p<1*10 -6 bold).
SDdifferences (95% CI) in platelet parameters compared to the reference category from multivariable linear regression models including each platelet parameter as an outcome variable (sex-specific z-scores, following log-transformation) and as exposures, ABSI-by-HI ("pear" reference) and BMI categories (model A), or BMI-by-ABSI-by-HI ("pear" NW reference) (model B), with adjustment for height, age, weight change (last year), smoking status, alcohol consumption, physical activity, Townsend deprivation index, region of the assessment centre, time of blood collection, fasting time, use of nonsteroidal anti-inflammatory drugs, paracetamol use, and for women, menopausal status, hormonal replacement therapy use, oral contraceptives use, and age at the last live birth. Plots are shown in Figure 3.
p shape / shape-by-size -p-values for the association with body shape overall (shape) or for heterogeneity of the associations with body shape according to BMI category (shape-by-size), from likelihood ratio tests (separately for women and men), comparing fully adjusted models including BMI categories with and without ABSI-by-HI (shape), or the fully adjusted additive model including ABSI-by-HI and BMI categories, with the interaction model including BMIby-ABSI-by-HI (shape-by-size) (p<1*10 -6 bold).
p sex shape / sex shape-by-size -p-values evaluating men vs women, from likelihood ratio tests comparing models including women (reference) and men with and without an interaction term of ABSI-by-HI (sex shape) or BMI-by-ABSI-by-HI (sex shape-by-size) with sex, adjusted for covariates (except female-specific), and including an interaction term of age with sex (p<1*10 -6 bold).
SDdifferences (95% CI) in platelet parameters per one SD increment of ABSI or HI from multivariable linear regression models including each platelet parameter as an outcome variable (sex-specific z-S14 scores, following log-transformation) and BMI, ABSI, and HI as exposure variables (sex-specific zscores), with adjustment for height, age, weight change (last year), smoking status (for models by alcohol consumption), alcohol consumption (for models by smoking status), physical activity, Townsend deprivation index, region of the assessment centre, time of blood collection, fasting time, use of nonsteroidal anti-inflammatory drugs, paracetamol use, and for women, menopausal status, hormonal replacement therapy use, oral contraceptives use, and age at the last live birth.
Separate analyses were performed within subgroups by alcohol consumption and smoking status, individually for women and men.
A p-value for the interaction terms of ABSI and HI with sex, from a model including women (reference) and men, with adjustment for BMI and covariates (except female-specific), and including an interaction term of age with sex, to account for potential differences by menopausal status in women.
W / M p-value (women / men) derived from likelihood ratio tests comparing models with and without interaction terms of either ABSI or HI with either alcohol consumption or smoking status, separately for women and men, with adjustment for BMI and covariates.
p-values -p≥0.05; * p<0.05; ** p<0.001; *** p<1*10 -6  MPV -mean platelet volume; PDW -platelet distribution width; Post-MP -post-menopausal women; Pre-MP -pre-menopausal women; SD -standard deviation. S18 SD difference (95% CI) in platelet parameters per one SD increment of BMI, ABSI, or HI from multivariable linear regression models including each platelet parameter as an outcome variable (sex-specific z-scores, following log-transformation) and BMI, ABSI, and HI as exposure variables (sex-specific z-scores), with adjustment for height, age, weight change within the last year preceding recruitment (main analysis only), smoking status, alcohol consumption, physical activity, Townsend deprivation index, region of the assessment centre, time of blood collection, fasting time, use of nonsteroidal anti-inflammatory drugs, paracetamol use, menopausal status (women overall), hormonal replacement therapy use (women overall and Post-MP), oral contraceptives use and age at the last live birth (all women).
The plots show a sensitivity analysis, restricted to participants with self-reported stable weight within the last year preceding recruitment, in comparison to the main analysis. S19 Fig. S4 Associations of anthropometric indices with platelets in participants without NSAID or paracetamol use ABSI -a body shape index; BMI -body mass index; CI -confidence interval; HI -hip index; MPV -mean platelet volume; NSAID -non-steroidal anti-inflammatory drugs; PDW -platelet S20 distribution width; Post-MP -post-menopausal women; Pre-MP -pre-menopausal women; SDstandard deviation.
SD difference (95% CI) in platelet parameters per one SD increment of BMI, ABSI, or HI from multivariable linear regression models including each platelet parameter as an outcome variable (sex-specific z-scores, following log-transformation) and BMI, ABSI, and HI as exposure variables (sex-specific z-scores), with adjustment for height, age at recruitment, weight change (last year), smoking status, alcohol consumption, physical activity, Townsend deprivation index, region of the assessment centre, time of blood collection, fasting time, use of nonsteroidal anti-inflammatory drugs and paracetamol (main analysis only), menopausal status (women overall), hormonal replacement therapy use (women overall and Post-MP), oral contraceptives use and age at the last live birth (all women).
The plots show a sensitivity analysis, restricted to participants receiving no NSAIDs and no paracetamol, in comparison to the main analysis.